The delivery of sufficient oxygen and metabolic precursors for the continued function of the heart is critically dependent upon a sufficient blood supply. Unlike most organs of the body the heart extracts almost all available oxygen from the capillary blood and has minimal anaerobic capacity. Any increases in oxygen demand by the heart muscle therefore be met by an immediate increase in blood flow. Even a brief interuption of blood flow can lead to ischemia. An understanding of the mechanisms by which coronary vascular tone is regulated is thus of immediate importance to our understanding of the physiology and pathology of the heart. The proposed study investigates the relationship of membrane potential to tension development in the in vitro guinea-pig coronary artery as a means of understanding the mechanism by which nerves and myocardial metabolic activity control coronary artery tone. Experiments have been designed to 1) characterize the membrane electrical responses in smooth muscle cells elicited by perivascular nerve stimulation including excitatory junction potentials, action potentials and slow depolarization or hyperpolarization; 2) determine what type of nerves (adrenergic? cholinergic?) are responsible for the observed membrane responses; 3) correlate neurally induced electrical activity with contraction to determine what constitutes an effective contractile stimulus; 4) investigate the mechanism of action of several metabolically related stimuli (i.e., adenosine, bradykinin, prostacyclin, potassium and reduced O2) currently thought to have a role in matching myocardial O2 demand with coronary blood flow; 5) investigate the interaction which occurs when neural and metabolically related stimuli occur simultaneously to determine how one modality overrides the actions of the other; 6) investigate the mechanism of action of a physiologically activated vasodilating substance obtained from the perfusate of a metabolically stressed guinea-pig heart and compare its actions to the proposed metabolic mediators. With these studies we hope to further elucidate the mechanisms by which coronary blood flow is regulated. By understanding how a balance is accomplished between factors initiating vasodilation and factors initiating vasoconstriction we may also provide new insights into how the balance becomes disturbed during the pathological condition of coronary spasm, an increasingly recognized cause of myocardial ischemia, infarction and sudden death.